Abstract ：

Depression is a common mental disease that can lead to suicide when severe. Exposure to prenatal stress (PS) can lead to depression-like behavior in offspring, but the mechanism is unclear. RhoA (Ras homology family member A) plays an important role in stress-induced changes in synaptic plasticity, ...

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depression-like behavior prenatal stress RhoA ROCK1/2 simvastatin

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Pancreatic ductal adenocarcinoma (PDAC) is a disease with no effective therapeutics. A novel targeted therapy drug consisting of a tumor-targeting ligand, near-infrared (NIR) organic heptamethine carbocyanine dye (DZ), and HMG-CoA inhibitor simvastatin (SIM), is developed and its efficacy in PDAC is assessed. PDAC cell specific targeting of DZ-SIM is measured by determining the fluorescence in cells and animals. Mitochondrial bioenergetics and functions are measured by Seahorse and flow cytometry, respectively. Apoptosis is assessed by DNA fragmentation, annexin V/propidium iodide staining, and TUNEL. Markers of cell invasion, epithelial-to-mesenchymal transition, and cancer stemness are measured. The effect of DZ-SIM on survival, tumor growth, and metastasis is measured in the Kras( thorn /LSLG12D);Trp53( thorn /LSLR172H);Pdx-1(-Cre) transgenic mice and in syngeneic and subcutaneous PDAC models. NIR fluorescence imaging shows specific localization of DZ-SIM to cancer, but not to normal cells and tissues. DZ-SIM significantly inhibits tumor growth and re-sensitizes therapeutically resistant PDAC cells to conventional therapies. DZ-SIM kills cancer cells through unique pathways involving decreasing mitochondrial bioenergetics, including oxygen consumption and ATP production, and increasing ROS production. Mitochondrial depletion prevents the effect of DZ-SIM. Administration of DZ-SIM in three PDAC animal models results in a marked increase in survival and a decrease in tumor growth and metastasis.

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mitochondria pancreatic cancer Simvastatin

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Background: Abnormal blood lipids are associated with cognitive impairment and amyloid-beta (A beta) deposition in the brain. However, the effects of statins on Alzheimer's disease (AD) have not been determined. Objective: Considering that plasma A beta are related to A beta deposition in the brain, we investigated the effects of simvastatin on plasma A beta transport. Methods: This was a randomized, double-blind, placebo-controlled trial. One hundred and twenty patients with hyperlipidemia were randomly assigned to receive 40 mg of simvastatin per day or matching placebo for 12 weeks (sixty patients per group). Plasma A beta, sLRP1, sRAGE, and lipid levels were measured at baseline and at the 6-week and 12-week visits. Results: The ITT database ultimately included 108 participants (placebo group: n = 53; simvastatin group: n = 55) and 64 (59.3%) were women, ranging in age from 45 to 75 years (mean 57.2 +/- 6.9 years). Multiple linear regression analysis showed that, after 12 weeks of follow-up, compared with the placebo group, Delta A beta(42) levels (the change of A beta(42) levels from baseline at week 12) increased more and Delta sRAGE levels decreased more in the simvastatin group (A beta(42): beta = 5.823, p = 0.040; sRAGE: beta = -72.012, p = 0.031), and a significant negative association was found between Delta A beta(42) and Delta sRAGE levels (beta = -0.115, p = 0.045). In addition, generalized estimation equation analysis showed that triglycerides levels were negatively correlated with A beta(40) (beta = -16.79, p = 0.023), A beta(42) (beta = -6.10, p = 0.001), and sRAGE (beta = -51.16, p = 0.003). Conclusion: Daily oral simvastatin (40 mg/day) in patients with hyperlipidemia for 12 weeks can significantly increase plasma A beta(42) levels compared with placebo, which was associated with reduced triglycerides and sRAGE levels, indicating that statins may affect plasma A beta transport.

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Alzheimer's disease hyperlipidemia plasma amyloid-beta simvastatin soluble low-density lipoprotein receptor-related protein-1 soluble receptor of advanced glycation end products

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Background. The use of statins is a potential protective factor against the development of hepatocellular carcinoma. Therefore, we conducted a meta-analysis to evaluate the contribution of statins to the risk of hepatocellular carcinoma. Methods. We searched for PubMed and EMBASE through January 2021. Results. Thirty-two studies (eighteen cohort, eleven case-control, and three randomized controlled trials) reporting 56,838 cases of hepatocellular carcinoma in 4,963,518 persons were included. Statin users were less likely to develop hepatocellular carcinoma than nonusers (adjusted odds ratio, 0.58; 95% CI: 0.51-0.67). Stratified analysis showed that statins reduced the risk of hepatocellular carcinoma in Asian and Western populations (odds ratio, 0.54 vs. 0.60). Besides, statins have protective effects against hepatocellular carcinoma after hepatitis B virus (odds ratio, 0.44; 95% CI: 0.22-0.85) and hepatitis C virus infections (odds ratio, 0.53; 95% CI: 0.49-0.57). Statins have protective effects on people with chronic liver disease (odds ratio, 0.52; 95% CI: 0.40-0.68) and on the general population (odds ratio, 0.60; 95% CI: 0.50-0.72). Lipophilic statins can prevent hepatocellular carcinoma (odds ratio, 0.51, 95% CI: 0.46-0.57), while hydrophilic statins cannot (odds ratio, 0.77, 95% CI: 0.58-1.02). The single-drug analyses showed that simvastatin (odds ratio, 0.53, 95% CI: 0.48-0.59), atorvastatin (odds ratio, 0.54, 95% CI: 0.45-0.64), rosuvastatin (odds ratio, 0.55, 95% CI: 0.37-0.83), lovastatin (odds ratio, 0.30, 95% CI: 0.15-0.62), and pitavastatin (odds ratio, 0.36, 95% CI: 0.17-0.75) had significant benefits. Further studies have shown that those in the high-dose group experienced better effects in preventing hepatocellular carcinoma (adjusted hazard ratio, 0.38 vs. 0.55). Further research found that the combined use of aspirin did not increase the chemoprevention effect of liver cancer (odds ratio, 0.57; 95% CI: 0.40-0.81). In addition, the preventive effect of statins improved with the extension of follow-up time (odds ratio, 0.54 vs. 0.65). Conclusion. Our meta-analysis shows that the use of statins is associated with a lower risk of liver cancer.

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Hyperlipidemia is one kind of metabolic syndrome for which the treatment commonly includes simvastatin (SV). Individuals vary widely in statin responses, and growing evidence implicates gut microbiome involvement in this variability. However, the associated molecular mechanisms between metabolic improvement and microbiota composition following SV treatment are still not fully understood. In this study, combinatory approaches using ultrahigh-performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF MS/MS)-based metabolomic profiling, PCR-denaturing gradient gel electrophoresis (PCR-DGGE), quantitative PCR (qPCR), and 16S rRNA gene sequencing-based gut microbiota profiling were performed to investigate the interplay of endogenous metabolites and the gut microbiota related to SV treatment. A total of 6 key differential endogenous metabolites were identified that affect the metabolism of amino acids (phenylalanine and tyrosine), unsaturated fatty acids (linoleic acid and 9-hydroxyoctadecadienoic acid (9-HODE)), and the functions of gut microbial metabolism. Moreover, a total of 22 differentially abundant taxa were obtained following SV treatment. Three bacterial taxa were identified to be involved in SV treatment, namely, Bacteroidaceae, Prevotellaceae, and Porphyromonadaceae. These findings suggested that the phenylalanine and tyrosine-associated amino acid metabolism pathways, as well as the linoleic acid and 9-HODE-associated unsaturated fatty acid metabolism pathways, which are involved in gut flora interactions, might be potential therapeutic targets for improvement in SV hypolipidemic efficacy. The mass spectrometric data have been deposited to MassIVE (https://massive.ucsd.edu/ProteoSAFe/static/massive.jsp). Username: MSV000087842_reviewer. Password: hardworkingzsr.

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gut microbiota high-throughput sequencing hyperlipidemia metabolomics simvastatin

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Multiple cancers have been reported to be associated with angiogenesis and are sensitive to anti-angiogenic therapies. Vascular normalization, by restoring proper tumor perfusion and oxygenation, could limit tumor cell invasiveness and improve the effectiveness of anticancer treatments. However, the underlying anticancer mechanisms of antiangiogenic drugs are still unknown. Metformin (MET) and simvastatin (SVA), two metabolic-related drugs, have been shown to play important roles in modulating the hypoxic tumor microenvironment and angiogenesis. Whether the combination of MET and SVA could exert a more effective antitumor effect than individual treatments has not been examined. The antitumor effect of the synergism of SVA and MET was detected in mouse models, breast cancer patient-derived organoids, and multiple tumor cell lines compared with untreated, SVA, or MET alone. RNA sequencing revealed that the combination of MET and SVA (but not MET or SVA alone) inhibited the expression of endothelin 1 (ET-1), an important regulator of angiogenesis and the hypoxia-related pathway. We demonstrate that the MET and SVA combination showed synergistic effects on inhibiting tumor cell proliferation, promoting apoptosis, alleviating hypoxia, decreasing angiogenesis, and increasing vessel normalization compared with the use of a single agent alone. The MET and SVA combination suppressed ET-1-induced hypoxia-inducible factor 1 alpha expression by increasing prolyl hydroxylase 2 (PHD2) expression. Furthermore, the MET and SVA combination showed a more potent anticancer effect compared with bosentan. Together, our findings suggest the potential application of the MET and SVA combination in antitumor therapy.

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angiogenesis ET-1 hypoxia metformin simvastatin

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Abstract ：

Depression is a common mental disease that can lead to suicide when severe. Exposure to prenatal stress (PS) can lead to depression-like behavior in offspring, but the mechanism is unclear. RhoA (Ras homology family member A) plays an important role in stress-induced changes in synaptic plasticity, participating in the development of depression by activating the downstream effector ROCK (Rho-associated protein kinase). This study explored the influence in the expression of RhoA and downstream molecules ROCK1/2 in prenatally stressed rats, and the effect of RhoA inhibitor simvastatin on depression-like behavior induced by PS. Depression-like behavior in offspring was detected by sucrose preference test, forced swimming test, and open-field test. The mRNA and protein expression of RhoA and ROCK1/2 in the hippocampus and prefrontal cortex of offspring rats were detected by qRT-PCR and western blotting, respectively. Our results showed that PS causes depression-like behavior in offspring rats, associated with elevated expression of RhoA, ROCK1/2 in the hippocampus and prefrontal cortex. After administration of simvastatin to PS rats, the expression of RhoA and ROCK2 was significantly reduced, alleviating depression-like behavior. Our study demonstrated that RhoA participates in the depression-like behavior in prenatally stressed offspring rats, which may be a potential target for antidepressant therapy. © 2022 Elsevier B.V.

Keyword ：

Depression-like behavior; Prenatal stress; RhoA; ROCK1/2; Simvastatin

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Objective: This national survey was aimed at measuring the access to cardiovascular disease (CVD) medicines in terms of their availability, price, and affordability in Pakistan. This was done by using the standard WHO/Health Action International (HAI) methodology. Methods: The price and availability data for 18 CVD medicines were collected from public sector hospitals (n = 40) and private sector retail pharmacies (n = 40) in eight cities of Pakistan. The outcome measures were availability (calculated as percentage of health facilities stocked with listed medicines), medicine price to the international reference price ratio (i.e., median price ratio (MPR)), and affordability (calculated as number of days' wages (NDWs) of the lowest paid unskilled government worker required to afford one-month treatment of a chronic disease). The affordability of standard treatment in Pakistan with four CVD drugs was compared with data from six other low and middle income countries (LMICs) using HAI database. Findings: The mean percent availability of CVD medicines was significantly low (p < 0.001) in the public sector as compared to the private sector, that is, 25.5% vs. 54.6% for originator brands (OBs) and 30.4% vs. 34.9% for lowest price generics (LPGs), respectively. For all OBs and LPGs, the inflation-adjusted mean MPR was 2.72 and 1, respectively. CVD medicines were found to be unaffordable with average NDWs of 6.4 and 2.2 for OBs and LPGs, respectively, that is, NDWs of more than 1. In international comparison with countries such as Sudan, Lebanon, Egypt, India, Afghanistan, and China, the affordability of standard treatment with selected CVD medicines (atenolol, amlodipine, captopril, and simvastatin) in Pakistan was found to be low. Overall, all four OBs and three out of four LPGs of selected CVD drugs were found unaffordable in Pakistan. Conclusion: This data indicated that the availability of selected CVD medicines was low in both public and private sector medicine outlets. Both OBs and LPGs were found unaffordable in the private sector, necessitating the redressal of pricing policies, structuring, and their implementation.

Keyword ：

access to medicines cardiovascular drugs essential medicines medicines policy non-communicable diseases

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Simvastatin, lovastatin, resuvastatin, pravastatin and cerivastatin belonging to statin family, which are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A. As the rate-limiting enzyme in the pathway of cholesterol metabolism, statins are classically prescribed to patients as lipid-lowering agents. However, statins also possess several extra bioactivities, which including anti-inflammatory, antiviral and anti-tumor.. Interestingly, the most essential mechanism of these activities is that statins could regulate the expression of cell adhesion molecules (CAMs), especially, targeting lymphocytes function associated molecules (LFA)-1, macrophage (Mac)-1 and intercellular adhesion molecules (ICAM)-1. Therefore, in this paper, we discussed the regulatory effect of statins on CAMs among different diseases. In addition, we provided a speculation for the role of statins in treating orthopedic disease.

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CAM cardiovascular disease inflammation LFA-1 Mac-1 Statins

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Abstract ：

Hyperlipidemia is a major risk factor for cardiovascular diseases. Simvastatin (SV), a cholesterol-lowering agent, has been widely used in the treatment of hyperlipidemia. Gut microbiota is known to influence drug response, including that to statins. However, the effect of SV on the gut microbiota of hyperlipidemic rats is not fully understood. To investigate the influence of SV on gut microbiota in hyperlipidemic rats, the molecular characterization of gut microbiota and the potential functions of genes involved in the downstream metabolic pathways were analyzed using high-throughput sequencing technology and the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States approach. The results revealed that SV treatment could reduce the gut microbial diversity and drive marked remodeling of the fecal bacterial community composition. At the phylum level, the relative abundance of Firmicutes and Actinobacteria was decreased following SV therapy, whereas that of Bacteroidetes was elevated. At the genus level, the percentage of the genera Bacteroides, Sutterella and Phascolarctobacterium was significantly increased, but that of Bifidobacterium, Ruminococcaceae_NK4A214, Ruminococcaceae_UCG-009, Intestinimonas and Tyzzerella was significantly decreased. Additionally, functional prediction analysis indicated that in the SV-associated microbiota, genes involved in energy, carbohydrate, amino acid and nucleotide metabolism likely exhibited enrichment. Briefly, to the best of our knowledge, the present study was the first to establish a profound and comprehensive association between the SV-induced alterations of the gut flora and the consequent influences of downstream metabolic pathways by gut microbiota. These findings suggested that the gut microbiota may contribute to the SV hypolipidemic efficacy in the progression of hyperlipidemia, which could provide insights for the prevention and treatment of hyperlipidemia.

Keyword ：

16S rRNA gene gut microbiota high-throughput sequencing hyperlipidemia hypolipidemic drug simvastatin

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